phase 2 trial assessing tbaj876 or bedaquiline, with pretomanid and linezolid in adults with drug-sensitive pulmonary tuberculosis

Conditions: Pulmonary TB; Pulmonary Tuberculosis; Drug Sensitive Tuberculosis

Summary: the goal of this clinical trial is to evaluate 3 dose levels of tbaj876 for 8 weeks in combination with pretomanid and linezolid, compared to 8 weeks of isoniazid, rifampicin, pyrazinamide and ethambutol (2hrze), in adult participants with newly diagnosed, smear-positive, pulmonary drug sensitive tuberculosis (ds-tb). the main questions the trial aims to answer are: * what is the optimal dose of tbaj876 to continue further in development. * what is the bactericidal activity of bedaquiline with pretomanid and linezolid (b-pa-l) compared to 2hrze and tbaj876-pa-l over 8 weeks * what is the efficacy and safety of the 26-week b-pa-l regimen compared with the soc (2hrze/4hr) in participants with ds-tb. participants will be seen regularly during treatment (up to 26 weeks) and follow-up (52 weeks post treatment) for safety and efficacy assessments, including but not limited to: * safety labs, ecgs, vital signs, physical exams, pk sampling, neuropathy assessments and adverse event monitoring * sputum collection

participants will be treated up to 26 weeks with either: * tbaj876 25 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by hr for 7 to 18 weeks * tbaj876 50 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by hr for 7 to 18 weeks * tbaj876 100 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by hr for 7 to 18 weeks * bedaquiline 200 mg + pretomanid 200 mg + linezolid 600 mg for 8 weeks followed by bedaquiline 100 mg + pretomanid 200 mg + linezolid 600 mg for 18 weeks * isoniazid (h) + rifampicin (r) + pyrazinamide (z), ethambutol (e) for 8 weeks followed by hr for 18 weeks (dose based on participant's weight). tbaj876 and bedaquiline will be blinded during the first 8 weeks of trial treatment; participants randomised to the tbaj876 or bedaquiline arms will receive open-label pretomanid and linezolid. participants randomised to the 2hrze/4hr arm will receive open-label hrze. after receiving 8 weeks of treatment, participants randomised to the tbaj876-pa-l treatment arms will receive open-label hr for at least 7 weeks. treatment completion will be allowed at week 15 in participants randomised to the tbaj876-pa-l arms, if the below criteria are met: * week 8 or eot make-up period 1 sputum mgit culture is negative, and * the participant has no tb-related symptoms by week 15. participants with symptoms that have a more likely alternative explanation are eligible to complete treatment at week 15. if the mgit result is mtb positive and/or there are still tb symptom(s), participants will continue to receive hr (in the 3 tbaj876 arms) and will complete 18 weeks of treatment with hr, for a total of 26 weeks of treatment. after receiving 8 weeks of trial treatment, all participants randomised to the hrze arm will receive open-label hr for 18 weeks, for a total of 26 weeks of treatment. after receiving 8 weeks of treatment, a participants randomised to the b-pa-l arm will receive open-label bedaquiline 100 mg (a reduction from the 200 mg daily dose in the first 8 weeks), pretomanid 200 mg, and linezolid 600 mg daily for 18 weeks, for a total of 26 weeks of trial treatment.

Eligibility criteria:
inclusion criteria: * signed informed consent * ds-tb as defined as sensitive to rifampicin and isoniazid by rapid sputum-based test and either newly diagnosed for tb or have a history of being untreated for at least 3 years after cure from a previous episode of tb * of non-childbearing potential or using effective birth control methods * body weight ≥ 35 kg exclusion criteria: * karnofsky score \< 60 at screening * any evidence of extrapulmonary tb * cardiovascular or qt prolongation risk factors * pregnant or breast-feeding any of the following lab toxicities: * platelets \<100,000/mm³ * creatinine \>1.3 x uln * haemoglobin \<9.5 g/dl or \<95 g/l * absolute neutrophil count \<800/mm³ * serum potassium less than the lower limit of normal for the laboratory. * alt and/or ast ≥2.5 x uln * total bilirubin ≥1.6 x uln * direct bilirubin \>1 x uln * haemoglobin a1c ≥8.0% * total lipase ≥1.5 x uln * total amylase ≥1.5 x uln * cpk \>3 x uln (if \>3 x uln, enquire about the participant's recent strenuous activity and consider repeating the test within the screening window) * tsh \>1 x uln * positive results at screening for hbsag, hav igm, or hepatitis c antibodies for participants living with hiv only: * cd4+ count\<200 cells/μl. * who clinical stage 4 hiv disease * participant does not agree to use dtg/tfv/3tc during trial if arv therapy is indicated, and randomised to the tbaj876 or the b-pa-l regimen * if initiation of arv therapy is indicate, participants who are known to be intolerant, non-responsive to dtg/tfv/3tc or have dtg/tfv/3tc as a contraindication.

Keywords: tbaj-876 tuberculosis pretomanid bedaquiline linezolid